Harold L Atkins1, Marjorie Bowman2, David Allan3, Grizel Anstee4, Douglas L Arnold5, Amit Bar-Or6, Isabelle Bence-Bruckler7, Paul Birch8, Christopher Bredeson3, Jacqueline Chen9, Dean Fergusson10, Mike Halpenny8, Linda Hamelin4, Lothar Huebsch7, Brian Hutton11, Pierre Laneuville12, Yves Lapierre13, Hyunwoo Lee13, Lisa Martin8, Sheryl McDiarmid4, Paul O'Connor14, Timothy Ramsay10, Mitchell Sabloff7, Lisa Walker15, Mark S Freedman16. 1. Ottawa Hospital Research Institute, Ottawa, ON, Canada; The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada. Electronic address: hatkins@ohri.ca. 2. Ottawa Hospital Research Institute, Ottawa, ON, Canada; The Ottawa Hospital MS Clinic, Ottawa, ON, Canada. 3. Ottawa Hospital Research Institute, Ottawa, ON, Canada; The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada. 4. The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada. 5. Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada; NeuroRx Research, Montreal, QC, Canada. 6. Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada; Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada. 7. The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada. 8. Ottawa Stem Cell Program, Canadian Blood Services, Ottawa, ON, Canada. 9. Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada; Department of Neurosciences, Cleveland Clinic, Cleveland, OH, USA. 10. Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada. 11. Ottawa Hospital Research Institute, Ottawa, ON, Canada. 12. McGill University Health Center, Montreal, QC, Canada; Division of Oncology, Department of Medicine, McGill University, Montreal, QC, Canada. 13. Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada. 14. Division of Neurology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada. 15. School of Psychology, University of Ottawa, Ottawa, ON, Canada; The Ottawa Hospital MS Clinic, Ottawa, ON, Canada. 16. Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada; The Ottawa Hospital MS Clinic, Ottawa, ON, Canada.
Abstract
BACKGROUND: Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis. METHODS: We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbitanti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930. FINDINGS: Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6-84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score. INTERPRETATION: We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease's aggressive nature. FUNDING: Multiple Sclerosis Scientific Research Foundation.
RCT Entities:
BACKGROUND: Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis. METHODS: We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930. FINDINGS: Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6-84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score. INTERPRETATION: We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease's aggressive nature. FUNDING: Multiple Sclerosis Scientific Research Foundation.
Authors: J Burman; K Kirgizov; K Carlson; M Badoglio; G L Mancardi; G De Luca; B Casanova; J Ouyang; R Bembeeva; J Haas; P Bader; J Snowden; D Farge Journal: Bone Marrow Transplant Date: 2017-03-20 Impact factor: 5.483